ACCESS TO ESSENTIAL ANTIBIOTICS AT ALL LEVELS OF CARE

4. ACCESS TO ESSENTIAL ANTIBIOTICS AT ALL LEVELS OF CARE

Essential antibiotics are those antibiotics needed to treat the most prevalent infectious diseases that affect that region. Essential antibiotics need to be iden- tified, listed, and secured at all levels of care at all times. This can be deter- mined by collecting data on morbidity and mortality due to infectious diseases and if possible by analysing surveillance data on key pathogens and their sus- ceptibility patterns. In addition, essential antibiotics can be classified accord- ing to spectrum of action, administration, cost, availability of generics, side effects, and ability to tolerate existing storage and transportation conditions.

Access to essential antibiotics can be influenced by many factors. In coun- tries where there is not a universal healthcare system, individual income level plays a major role in deciding what and when to purchase essential antibiotics. In most cases, only the privileged middle and upper class can obtain prescribed or unprescribed antibiotics. Studies conducted by Asturias and collaborators in Guatemala ascertained that middle and upper class families are more subject to issues of antimicrobial resistance due to an unrestricted access to antibiotics (Asturias et al., 2003). These individuals not only buy antibiotics when they please, but also get inadequate dosages and do not adhere to therapy guide- lines. There is not an understanding of the differences between improvement

602 Aníbal Sosa and cure of an infectious disease. In addition, as occurs in many other countries,

most antibiotic use is unjustified due to the viral etiology of most frequent infectious clinical episodes.

The poor on the other hand will depend on their own ability to purchase drugs or government assistance programmes such as social security dispensing systems that might be able to secure access to cheaper drugs such as properly stored and transported generics.

Developing countries in some instances choose not to respect product patents as they are the only effective means of making available pharmaceuti- cals necessary to save lives and protect the health of their citizens (Brock, 2001). In other instances, countries have the right to grant compulsory licenses to permit the manufacture of generic equivalents of patented drugs in situa- tions of national emergency or when negotiations have failed to ensure a fair price which would enable parties to satisfy their objectives of recouping investment costs and of maximally preventing avoidable deaths such as the case of HIV/AIDS (Schüklenk and Ashcroft, 2001). In November 2001, during the Fourth Ministerial Conference in Doha, Qatar, a declaration—the DOHA Declaration—was issued on international intellectual property laws. It helped deflect some of the effects of international patent protection policy. In the sec- tions dealing with TRIPS (trade-related aspects of intellectual property rights) governments agreed to allow certain countries to ignore worldwide patent pro- tection for certain drugs if the drugs are important to protecting public health (TRIPS, 2001).

Availability of antibiotics in developing countries is also influenced by other intrinsic factors such as counterfeited, expired, inactive, or substandard antibiotics (Hemming and Harvey, 1999). It is also common to find non-physi- cian healthcare workers, located in remote locations, who lack training to treat minor illnesses. Sometimes, these untrained practitioners are responsible for misuse of antibiotics (Okeke et al., 1999). In addition, the use of natural heal- ers, or “curanderos” is another reason that antibiotics are often used indiscrim- inately without the supervision of a trained pharmacist or practitioner.

4.1. Countries in the developing world with and without antibiotic policies

A quick electronic survey was emailed to APUA country chapter leaders in developing countries in Latin America, Africa, Asia, and Middle East. Thirteen responses were obtained and are presented in Table 5.

Developed countries are facing a large illegal distribution of prescription drugs by online unlicensed pharmacies, or the “swap meet” pharmacy where medications are sold for cash with no questions asked. Such illegal distribution

Antibiotic Policies in Developing Countries 603

Table 5. Sale, dispensing, and prescribing of antibiotics by illegal distributors and unsanctioned dealers of antibiotics

Country ATB Policy ATB Policy Antibiotic Unsanctioned,

Enforcement

Prescription Illegal dispensing or OTC of Law ATB

Argentina No

Yes Brazil

No

Yes

Yes Chile

No Colombia

Yes Costa Rica

Yes Dominican Republic

Yes Ecuador

No Guatemala

Yes Lebanon

No Nepal

Yes (OTC) Philippines

Yes (OTC) Taiwan

Yes Venezuela

Yes (OTC) Note: Over-the-counter (OTC) sale is prevalent in the majority of developing countries in

Latin America, and the Caribbean, Asia, and Africa.

of prescription medication is a booming business in the United States, Canada, and Europe (Unknown, 2002). In response, the US FDA has delineated plans to help curtail illegal marketing of prescription drugs on the Internet.

Unsanctioned dealers can often be found in developing countries. These are either individuals or groups operating in a nonexistent drug regulatory sys- tem. They are not considered illegal because they are not defined as such by any legal process. They are visibly tolerated and the community relies on them to obtain essential drugs. It is assumed that these drugs are not counterfeited, expired, or inactive, but there is no proof of a quality assurance system in place that guarantees the quality and purity of drugs sold.

In many parts of Africa, where antibiotics are commonly available from unsanctioned providers, it will be worth educating the general population about the consequences of irrational antibiotic resistance (Okeke and Sosa, 2003). Unsanctioned providers often reach out to people with limited access to orthodox healthcare, and are commonly not trained to diagnose infections or correctly pre- scribe appropriate doses. They serve as an unofficial outlet for many antibiotics, often capsules and tablets of cheaper antimicrobials, but are not limited to these. For example, Becker et al. (2002) recently described the inappropriate distri- bution of injectable antibiotics, including second- and third-line drugs such as oxacillin and third-generation cephalosporins, medicines that should be conserved for managing resistant infections.

604 Aníbal Sosa The use of subtherapeutic doses creates a situation where highly resistant

strains can be selected sequentially and this is a condition that prevails in many cases when antibiotics are used without proper prescription or in patient non- compliance. In addition, poor quality drugs can lead to treatment failure and consequently, excess mortality and morbidity (Prazuck et al., 2002). Poor quality drugs can provide subinhibitory selective pressure, of which neither the patient nor the prescriber are aware. Reports of substandard antibiotics have come from many countries and a significant proportion of these are in Africa. These reports describe preparations containing anything between 0–80% of stated label claim. Some of them contain such low concentrations that they can only be considered counterfeit, that is, deliberately manufactured with low or no active drug content. Others may have complied with pharmacopoeia standards at some time but have, in the course of distribution and display, been degraded by heat and humidity. Where possible, patients must be advised of the wisdom of obtaining medicines at reputable outlets, where they have been properly stored and where expiration and lot information is available (Okeke and Sosa, 2003). Prazuck et al. found similar findings in Northern Myanmar. Their findings suggest that public health policies based on national treatment guidelines should rigorously include the monitoring of quality control of available antimicrobial products. They found that only 3 of the 21 antimicrobials purchased to treat STD displayed the official “registered” label, 3 were expired, 6 did not have an expiration date, and 1 prod- uct did not contain the active principle and did not show any in vitro activity against bacteria. Seven of twenty-one products did not contain the stated dosage. In the absence of such measures, specific treatment strategies are likely to fail and to generate drug resistance (Prazuck et al., 2002).

Counterfeiting is a problem in India and the Philippines. India exports counterfeited drugs to the Middle East, southern Africa, and Europe causing serious threats to public health. Of the Philippine pharmaceutical market, 30% is estimated to be counterfeited drugs. Intellectual property protection in many developing and transition countries is inadequate which in turn makes it very difficult to implement the data exclusivity protection (Scrip, 2003).

Excessive use of antimicrobials in developing countries brings serious con- sequences for infections responsible for high infant mortality. These issues are very complex and must be addressed effectively with an aggressive approach that attacks the root causes (Gundersen, 1992).

4.2. Impact of donations of antimicrobials agents on country AMR policies

In general, drug donations to developing countries abide by international guidelines published in 1996 by WHO (WHO, 1996). Developed countries

Antibiotic Policies in Developing Countries 605 such as the United States, Australia, and Germany have specific bodies

charged with the task of ensuring certain criteria, and in particular making sure that donations match countries needs. Sometimes, drugs destined for a specific region or country, surface in another one by illegal practices of traders and wholesalers. This violates existing international regulations.

In 1999, the Medicines Crossing Borders Project issued a step-by-step guide called Good Drug Donation Practices (WHO, 2002); its main purpose is “to ensure the quality of donations once ready for shipment, or to evaluate a donation once made.”

Anti-infectives are the drugs most often donated. Donations of antimicro- bials as well as other drugs must be offered for as long as they are needed. For example, the provision of anti-retrovirals for HIV and AIDS often lacks conti- nuity and sustainability, jeopardising patient’s compliance and adherence. In turn, HIV resistance develops quite rapidly and patients are left with fewer options. Country health officials must have protocols for accepting drug donations to minimise inappropriate use and waste that will cost them money to dispose.

4.2.1. Reality-check of antimicrobial donations to developing countries

1. Donations do not always follow international guidelines; families living abroad often send antimicrobial agents for “just in case” infections usually defined by the presence of fever and/or purulent fluid (sputum in most instances).

2. Patients receive unnecessary or unacceptable antimicrobials.

3. In general, doses of antimicrobials donated by family members are incomplete.

4. Emergence of resistance is not easy to monitor; in some instances antimi- crobials received are fairly new in the market and not yet available in the country.

5. There is an increasing incidence of antibiotic-resistant pathogens in both hospitals and the community without a corresponding increase in new antimicrobial drugs.

In September 2002, The US Federal Interagency Task Force on Anti- microbial Resistance held a consultants meeting in San Diego, California (CDC, 2002). Their summary report, Input for A Public Health Action Plan to Combat Antimicrobial Resistance Part II: Global Issues, issued important recommendations in an attempt to curb antimicrobial resistance due to donated antimicrobials.

606 Aníbal Sosa

4.3. The decision-making process in prescribing antibiotic therapy

In the decision-making process for prescribing antibiotic therapy it is impor- tant to review scientific literature and guidelines issued from specialty societies. It is also important to consider other factors such as adverse drug reactions, aller- gies, pharmaco-economics, pharmacodynamics, pharmacokinetics, previous antibiotic therapy, treatment failures, and compliance issues. Primary care physi- cians are being increasingly challenged to take good care of our patients despite demands to keep costs down, get the patient well, and have prescribing habits profiled. In countries where government agencies subsidise drugs, prescribers are required to prescribe only what is listed in their formulary.

Irrational prescribing and over-prescribing of drugs is prevalent in many countries. Most prescribing in developing countries is performed by paramed- ical workers who only have minimal or no training at all (Holloway and Gautam, 2001). When studying antibiotic dispensing by drug retailers in Kathmandu, Nepal, Wachter et al. described the prescribers’ lack of adequate understanding of the disease processes in question (Wachter et al., 1999).

The government of Nepal spends 42% of the national health budget on drugs, while international donors spend nearly three times that amount. Drug distribution and use in Nepal is largely unregulated and the pharmaceutical industry is a major and growing market. Of the drugs, 80% are purchased out- side of the government-supplied health system, mostly through private retail shops and pharmacies. When antibiotics are prescribed, they are often not used correctly. Of all drugs prescribed in Nepal, 72% of scripts are not in compli- ance with standard norms and 38% of patients have misunderstood dosage and administration requirements.

4.4. Need for AMR surveillance data for key pathogens

The goal of surveillance of antimicrobial resistance is to provide the information necessary to secure an approach to the management of communi- cable diseases that minimises morbidity and mortality while also containing the emergence of pathogens resistant to antimicrobials. Surveillance of antimi- crobial resistance must involve the collection and collation of both clinical and microbiological data. Surveillance of prevalent bacterial pathogens and sus- ceptibility profiles can be an expensive endeavour that few local, regional, or national institutions can afford; however, availability of AMR surveillance data can be useful in prescribing the most effective available antibiotic. It is impor- tant that each country has in place minimal requirements for an effective surveillance system.

Antibiotic Policies in Developing Countries 607 Significant differences in susceptibility profiles within one pathogen, such

as clinical isolates of Pseudomonas aeruginosa in two countries in South America (Venezuela and Paraguay), generate important implications. There is

a need to monitor antimicrobial resistance at the local level that serve as an alert for clinicians and public health officials (Rodriguez et al., 2002). Emergence of multidrug resistant pathogens calls for a proactive approach. Sentinel surveillance is useful in high-risk areas.

In 1993, Nepal instituted an AMR intervention that began by having an external contractor (ICDDR, B) assessing the microbiology infrastructure and capabilities to perform antibiotic susceptibility testing (AST). They have been collecting bacterial isolates, identifying them and performing internal and external quality assurance and AST to determine if they are resistant to rele- vant antimicrobials (Sosa and Stelling, 2003). These antimicrobial resistance surveillance efforts have focused on five priority pathogens: Shigella sp, Vibrio cholerae, Neisseria gonorrhoeae, Streptococcus pneumoniae, and Haemophilus influenzae.

4.4.1. Translating AMR surveillance data into action

AMR surveillance data can be used to make decisions about treatment at the clinical level and decisions about drug policy at the national level. For example, resistance of a pathogen to an antimicrobial often results in treatment failure so the detection of this resistance should lead to a recommendation to avoid using this antimicrobial for therapy. Sudha et al. have come up with pro- posed criteria for choosing empiric antimicrobial therapy based on the sensi- tivity index (SI) value in relation to prevalence of resistance. SI can be defined as the ratio of per cent susceptible to per cent nonsusceptible strains of microorganism in a particular region during a specific time period (Sudha et al., 2003). This method could be useful for countries in the developing world; however, caution must be exercised since this approach needs to be validated.

Another approach could be the determination of Resistance Alert Thresholds (RAT). This approach, though controversial, remains elusive since RAT values need to be assigned arbitrarily using resistance prevalence data for key pathogens (Tapsall, 2001).

4.5. Effectiveness and cost-effectiveness of measures to contain antimicrobial resistance

In 2002, Wilton et al. reviewed 43 studies, mainly hospital-based, from the United States. Some of these studies had community level interventions. These studies covered policies on: restricting the use of antimicrobials (five studies,

608 Aníbal Sosa suggesting that restriction policies can alter prescriber behaviour, although

with limited evidence of subsequent effect on AMR); prescriber education, feedback, and use of guidelines (six studies, with no clear conclusion); combi- nation therapies (seven studies, showing the potential to lower drug-specific resistance, although for an indeterminate time period); vaccination (three stud- ies showing cost/effectiveness). Important conclusions are derived from this analysis, and particularly for developing countries (Wilton et al., 2002).

Public health officials, policy-makers, and clinicians can customise local antibiotic policies that have the potential to significantly impact AMR and reduce its burden in terms of cost, morbidity, and mortality. Drug and Therapeutic Committees (DTCs) are usually charged with this task.

High-risk hospital areas are hard hit by nosocomial infections and multidrug-resistant (MDR) pathogens. Emergence of MDR Acinetobacter ani- tratus species in neonatal and paediatric intensive care units in Durban, South Africa, caused 56.5% mortality. Most of the infants had received broad- spectrum antibiotics considered a risk factor for acquiring MDR (Jeena et al., 2001). A variation of a restrictive antibiotic policy is the use of a directive policy-driven letter targeted to a specific antibiotic. This type of intervention sends instructions to prescribers to discourage the use of an antibiotic. Changes in prescribing practices can be observed; however, if reason for change is not fully described, unexpected, untoward results (increase in mor- bidity and cost) can also be encountered and can be counterproductive (Beilby et al., 2002).

Drug and Therapeutic Committees offer practical approaches for promot- ing rational use of drugs. Key responsibilities include formulary management, STGs, essential drug list (formulary list), indicators of rational use of drugs, and interventions to change inappropriate use of drugs. They are a meeting ground between clinicians, pharmacists, and financial managers to negotiate the balance between cost and quality.

Drugs and Therapeutic Committees are charged with the responsibility of designing STGs to assist prescribers in choosing the most appropriate antimi- crobials. These guidelines can address syndromes or be disease-specific. They can provide first-, second-, and third-line antibiotics according to a country’s list of essential drugs described in the national formulary.

A study by Sosa et al. of physician prescribing practices in seven countries in Latin America and the Caribbean focused on physician knowledge, attitude, and behaviour as a way to quickly begin understanding and working on the resistance problem. The study illustrated that (1) there exists an acute need to raise physi- cian awareness regarding resistance patterns in key pathogens; (2) there is a gen- eral lack of information for physicians to appropriately treat ARIs and acute diarrhoeal diseases empirically; (3) there is a significant need for the collection

Antibiotic Policies in Developing Countries 609 and dissemination of more local AB resistance data to improve prescribing

patterns and patient outcomes; (4) reference laboratories are either lacking and/or physicians are unaware of their existence (62.9% stated that they do not have access to such a lab); and (5) physician training on antibiotics in Latin America had no significant effect on appropriate antibiotic usage (Sosa and Travers, 2001). We have often experienced that AMR surveillance data are not appropriately disseminated among prescribers and decision-makers.

The classical example of combination antimicrobial therapy is the use of combined antimicrobial drugs for the treatment of TB. Combination therapy is also the primary method of treating febrile neutropenia, infections involving multiple organisms, and for obtaining synergism and preventing or limiting resistance development. It is also used in other critical infections such as HIV/AIDS, malaria, sepsis by Gram-negative bacteria, nosocomial infections, and cystic fibrosis. Use of Direct-Observed-Therapy Short Course (DOTS)- Plus to treat multidrug resistance TB has proven to be more effective than DOTS alone. DOTS-Plus uses second-line antituberculosis drugs considered “reserve or second line.” Second-line agents that would be used under DOTS- plus are more expensive, more difficult to administer and often poorly toler- ated. Although controversial, it does cause fewer deaths (Sterling et al., 2003).

Drug combinations have a downside in that they increase the potential for drug related side effects, the likelihood of colonisation by resistant organisms, and the possibility of antagonism between the agents (Cunha, 2003). When using initial empiric combination therapy for hospital-acquired infections, patient outcomes could be be improved (Kollef, 2001). In general, single, nar- row-spectrum antibiotic therapy is more appropriate in community-acquired infections.

Several infectious microorganisms including S. pneumoniae and H. influenzae are serious pathogens in children under the age of 5, causing pneumonia and meningitis, respectively. These bacteria possess virulence mechanisms able to cause high morbidity and mortality. In addition, both have acquired resistance to many antimicrobial agents. In developing countries, immunisation can reduce the use of antimicrobials and hence the emergence of antimicrobial resistance (O’Dempsey et al., 1996).

The widespread use of vaccination for S. pneumoniae and H. influenzae could reduce the need for antibiotics in infants and toddlers through:

● Reduction in the need to cover potential invasive pathogens in acute febrile episodes

● Reduction in respiratory tract morbidity ● Potential reduction in non-responsive episodes ● Reduction of carriage and spread of antibiotic-resistant organisms.

610 Aníbal Sosa No effective reduction in antibiotic use will occur, however, without

additional appropriate measures ● Education of medical teams

● Education of the community ● Providing legal protection to those withholding antibiotics by redefining the

“reasonable physician.” An S. pneumoniae surveillance network was started in 1994 in six Latin

American countries (SIREVA-Vigía project) coordinated by the Pan- American Health Organization. This regional initiative was designed to obtain information about the S. pneumoniae serotype distribution in order to deter- mine the ideal composition for a conjugate vaccine that could be useful for the region. Additionally, the project was aimed at monitoring the rates of S. pneumoniae antimicrobial resistance (Gamboa et al., 2002). This pro- gramme has identified high levels of antibiotic resistance in Latin America that call for the development of rational antibiotic use guidelines.

4.6. Consumer awareness

Educational campaigns can effectively reduce antibiotic use and ultimately, antibiotic resistance rates. An intervention conducted in the United States resulted in a decrease in antibiotic prescribing for bronchitis, from 74% to 48%, compared to a 2% decrease at control/limited intervention sites (Gonzales et al., 1999). Successful integrated approaches have been carried out in India, Indonesia, and Pakistan (Tawfik, 2000) combining a Verbal Case Review (VCR) and a tool called Information Sharing, Feedback, Contracting, and Ongoing Monitoring (INFECTOM). The approach successfully educated prac- titioners in those countries about standard protocols, and compared their knowledge with actual practices. The results indicate that ongoing monitoring helps to encourage consistent improvement in prescribing practices. To influ- ence parents, another approach could be to field test an antibiotic use and resistance curriculum for elementary and high schools.

4.7. Training of healthcare workers and other individuals

Justifying training of non-medical providers (healthcare workers, for instance) could be controversial; however, the reality is that most physicians in

a developing country are located in the capital where most of the population also resides. The presence of unskilled practitioners in remote rural areas calls

Antibiotic Policies in Developing Countries 611 for training them in approaches similar to one used by WHO Integrated

Management of Children Illnesses (IMCI) which calls for non-physician health workers (HWs) to evaluate every sick child presenting to a first-level health facility (HF) for respiratory infections, diarrhoea, malaria, measles, and malnutrition, regardless of the child’s presenting complaint(s). To find out effectiveness of the IMCI approach, a study was conducted to evaluate the level of performance achieved by IMCI-trained HWs at the end of training and the level of performance maintained during the first 3 months post-training with monthly or bimonthly clinical supervision. They found that HWs achieved reasonably high performance levels managing ill children with mild and moderate disease classifications but performed at a much lower level when managing severely ill children at the end of training (Odhacha, 1998). In 2001, WHO conducted an evaluation of the cost, effectiveness, and impact of IMCI in Tanzania, Uganda, Bangladesh, and Perú. Results from Tanzania showed that baseline data on mortality, family practices, and care seeking for sick children demonstrated that IMCI is addressing the most common major health problems of children in the study illnesses: malaria, pneumonia, and diarrhoea. The prevalence of anaemia, though, was very high, with almost 10% of children between the ages of 6 and 12 months having life-threatening anaemia (WHO, 2001).